Dietary fat promotes overeating and obesity. Our recent studies demonstrate that ingestion of fat and the resulting rise in circulating lipids stimulate the hypothalamic peptide, galanin. In turn, higher galanin peptide further enhances food ingestion, particularly of high-fat diets. These findings lead to the novel suggestion that there exists a positive feedback loop, involving dietary fat, circulating triglycerides (TG) and hypothalamic peptides, which functions in a non-homeostatic manner to promote the overeating of fat-rich foods. This positive loop pre-empts and delays the effective onset of homeostatic negative feedback signals that normally limit food intake. Preliminary studies suggest that the opioid peptides, enkephalin and dynorphin, may also be involved in this process, acting in a remarkably similar way to galanin. Further, these hypothalamic peptides may be related to dopamine (DA) in the nucleus accumbens, which is known to enhance the motivation to eat. This new body of evidence leads us to propose the following six Specific Aims designed to test the specific role of hypothalamic peptide systems, accumbens DA, and lipids in promoting overeating of a high-fat diet. We plan: 1) To use acute, experimental paradigms to more precisely test in rats the involvement of circulating lipids in the well-known stimulatory effect of dietary fat on total caloric intake; 2) To firmly establish the effect of dietary fat and endogenous TG on specific hypothalamic peptides; 3) To study the role of accumbens DA in the effects of hypothalamic peptides and dietary fat on caloric intake; 4) To define the neural substrates and establish their essential nature in the phenomenon of fat-induced hyperphagia; 5) To investigate normal-weight outbred rats that are prone to overeating a fat-rich diet, to determine if they exhibit disturbances in these neurochemical systems; and 6) To examine whether brief periods of exposure to a high-fat diet early in life can have long-term impact on the peripheral and brain systems that control ingestion of a high-fat diet later in life. In summary, this grant tests the novel hypothesis that a high-fat diet itself can promote overeating and ultimately dietary obesity through a positive feedback loop involving circulating lipids, hypothalamic peptides and accumbens DA. [unreadable] [unreadable]